Improvement of intestinal absorption of leucine enkephalin by sugar coupling and peptidase inhibitors.

Peptidase-degradable leucine enkephalin (LE) was coupled with cellobiose or gentiobiose. In the absorption experiments, cellobiose-coupled LE (CcpLE) was more stable than LE itself on the mucosal side, and CcpLE appeared on the serosal side. Destyrosyl LE coupled with cellobiose was not formed, indicating that sugar coupling provided LE with aminopeptidase resistance. In the presence of inhibitors of angiotensin-converting enzyme and enkephalinase, the stability of CcpLE on the mucosal side was increased, and as a result more was absorbed. Furthermore, the absorption clearance was much higher than the value expected from the mucosal concentration of CcpLE. Similar results were observed in the absorption of gentiobiose-coupled LE. In the LE absorption experiment, however, LE was not detected on the serosal side even in the presence of these peptidase inhibitors. Improvement of intestinal absorption by sugar coupling and peptidase inhibitors was evaluated kinetically, indicating the exclusive contribution of metabolic degradation of LE through intestinal tissues to the absorption process.